Racemization and asymmetric transformation processes used in the manufacture of levobupivacaine and analogues thereof

ABSTRACT

A process for the racemisation of an optically-enriched piperidine-2-carboxanilide compound, comprises heating the compound in the presence of an alkanoic or arylalkanoic acid. A process for the asymmetric transformation of such a compound comprises heating the compound in the presence of an acid as defined above, a chiral acid resolving agent and an inert cosolvent.

This application is a 371 of PCT/GB95/02247 which is now published asWO96/09290.

1. Field of the Invention

This invention relates to the racemisation and dynamic resolution ofoptically-enriched heterocyclic carboxanilides, e.g.piperidine-2-carboxanilides such as levobupivacaine.

2. Background of the Invention

Compounds of formula 1 (see formulae, below) wherein R¹ is methyl,n-propyl, n-butyl or cyclopropyl and R² is a 2,6-dimethylphenyl haveutility as local anaesthetics. Biological studies have shown that(S)-enantiomers of such compounds display lower cardiotoxicity than thecorresponding racemates whilst maintaining the same anaesthetic potency,and are therefore potentially more beneficial for clinical uses. Thusthere is a requirement for efficient processes to manufacture compoundsof formula 1 in the form of single enantiomers. For this purpose,conventional resolution approaches invariably afford up to 50% of theunwanted enantiomer. To improve atom utilisation in such processes, itis desirable to recycle the unwanted enantiomer by effecting itsracemisation to provide material suitable for subsequent resolution.Additional benefits may be attainable by "asymmetric transformation",comprising simultaneous racemisation and crystallisation-inducedresolution in a one-pot process.

Fyhr et al, Acta Pharm. Suecica 25(3):121-132 (1988), disclose theracemisation of ropicavaine hydrochloride (1.HCl, R¹ =n-propyl, R²=2,6-dimethylphenyl, absolute configuration =S) in dilute aqueoussolution at pH 1-6, using HCl, and 80°-130° C. The results are presentedas a preformulation stability study and merely serve to indicate thatropivacaine racemises slowly in aqueous media.

Shiraiwa et al, Bull. Chem. Soc. Jpn. 64:3251-3255 (1991), discloseasymmetric transformation of 2-piperidine-carboxylic acid, by heating inan alkanoic acid solvent in the presence of an chiral acid resolvingagent and an aldehyde. The latter component is believed to assistracemisation by formation of a cationic Schiff base intermediate, amechanistic pathway which can also operate onpiperidine-2-carboxanilides 1 only in cases where R¹ =H. Again, thisprocess is unsuitable for operation on a manufacturing scale, not leastbecause it uses environmentally-unacceptable reagents.

SUMMARY OF THE INVENTION

The present invention is based on the surprising discovery thatN-heterocyclic-2-carboxanilides, including compounds of formula 1wherein R¹ is H, methyl, n-propyl, n-butyl or cyclopropyl and R² isphenyl optionally substituted with one or more methyl groups, undergorapid racemisation when heated in solution in the presence of acarboxylic acid R³ CO₂ H wherein R³ is either n-alkyl or aryl(exemplified in Scheme 1) or any acid having a pKa of -1 to +6, relativeto water. The reaction can be carried out in a wholly or substantiallynon-aqueous system, e.g. either in a solution of neat acid or in thepresence of an inert cosolvent such as xylene or toluene. The presenceof residual salt forms of compounds of formula 1, e.g. as the result ofresolution using a chiral resolving agent, do not impede the efficiencyof the process.

A preferred embodiment of the invention is the racemisation ofbupivacaine (1, R¹ =n-butyl, R² =2,6-dimethylphenyl) enriched in oneenantiomer, preferably the (R)-enantiomer, by heating with propanoicacid or butanoic acid. A suitable cosolvent such as xylene allows thereaction to be conducted at optimum temperature, i.e. about 130° C.Compared to the prior art, this process, and processes of the inventionin general, afford significant advantages since neither dilute aqueoussolutions ( 1!<50 mM) nor extended reactions times are required.

As a further feature of the invention, it has been discovered thatasymmetric transformation of the N-heterocyclic-2-carboxanilides can beachieved by including a chiral acid resolving agent as an additionalcomponent in the processes described above (exemplified in Scheme 2).

Two variants of such transformations are possible: firstly, a one-potprocess in which a given enantiomer of the carboxanilide is converted toits optical antipode by heating to effect racemisation, followed byaddition of a chiral acid, resulting in diastereoselectivecrystallisation of a salt; and secondly, the use of pre-formed racemiccarboxanilide as a starting material. Any suitable chiral acid can beused; examples include L- and D-tartaric acid, and O,O-dibenzoyl andO,O-ditoluoyl derivatives thereof; (R)- and (S)-10-camphorsulphonicacid;

(R)- and (S)-mandelic acid; (R)- and (S)-malic acid; (R)- and(S)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate; and abietic acid.

An important aspect of this invention relates to the ability to operatethe process on an industrial scale.

This in turn means that the optically-enriched carboxanilidesthemselves, e.g. obtained by resolution but to an extent that thepredominant enantiomer is insufficiently enantiopure for immediate use,become useful products. This applies to mixtures of enantiomers in whichone, usually the (R)-enantiomer, is present in an enantiomeric excess of20 to 80%, preferably 25 to 75%, more preferably 30 to 70%, and mostpreferably 35 to 65%, with respect to its optical antipode. For example,a mixture enriched in (R)-bupivacaine can be used practically, byracemisation of the mixture and subsequent resolution.

The following Example illustrates the invention.

EXAMPLE

A stirred mixture of (S)-bupivacaine (0.140 g, 0.49 mmol) and propanoicacid (3.5 ml) was heated to reflux under a nitrogen atmosphere for 7hours. The resulting solution was cooled and then poured into a mixtureof distilled water (20 ml) and ethyl acetate (20 ml). Aqueous ammonia(28% w/v) was added until the pH of the aqueous layer was 10. Theorganic layer was separated and the aqueous layer extracted with ethylacetate (20 ml). The combined organic extracts were washed withdistilled water (20 ml), dried (MgSO₄) and concentrated under reducedpressure to give racemic bupivacaine (0.137 g, 98%). ##STR1##

We claim:
 1. A process for the racemisation of an optically-enrichedN-containing heterocyclic compound having 3 to 7 ring atoms and acarboxanilide group attached to the ring at a carbon atom in the2-position adjacent to the N-atom, said carbon atom being the chiralcenter to be racemised, wherein said N-atom is substituted with an R₁substituent and said R₁ substituent is not H, said method comprisingheating the compound in a wholly or substantially non-aqueous systemcomprising an acid selected from the group consisting of alkanoic acids,arylalkanoic acids and acids having a pKa of -1 to +6, relative towater.
 2. The process according to claim 1, wherein the compound is apiperidine-2-carboxanilide.
 3. The process according to claim 1, whereinthe compound is of formula (1)wherein R¹ is a substituent of up to 20 Catoms and R² is alkyl or aryl of up to 20 C atoms.
 4. The processaccording to claim 3, wherein R² is C₆₋₂₀ aryl.
 5. The process accordingto claim 4, wherein R¹ is C₁₋₆ alkyl and R² is phenyl optionallysubstituted with one or more C₁₋₄ alkyl groups.
 6. The process accordingto claim 5, wherein the starting material is optically-enrichedbupivacaine, wherein R¹ is n-butyl and R² is 2,6-dimethylphenyl.
 7. Theprocess according to claim 6, wherein the starting material is enrichedin the (R)-enantiomer.
 8. The process according to claim 5, wherein R¹is selected from the group consisting of methyl, n-propyl andcyclopropyl and R² is 2,6-dimethylphenyl.
 9. The process according toclaim 1, wherein the racemisation is carried out in a solution of theacid, neat or mixed with an inert cosolvent.
 10. The process accordingto claim 9, wherein a solution of optically-enriched bupivacaine isheated in propanoic acid or butanoic acid.
 11. A process for theasymmetric transformation of a compound as defined in claim 1, whichcomprises heating the compound in the presence of an acid selected fromthe group consisting of alkanoic acids, arylalkanoic acids and acidshaving a pKa of -1 to +6, relative to water, a chiral acid resolvingagent, and an inert cosolvent.
 12. The process according to claim 11,wherein the compound, optically-enriched in a given enantiomer, isconverted to its optical antipode.
 13. The process according to claim11, wherein said racemic compound is transformed.
 14. The processaccording to claim 1, wherein the acid is an alkanoic or arylalkanoicacid.
 15. The process according to any of claim 1, wherein the acid hasthe given pKa.
 16. The mixture of enantiomers of a compound as definedin claim 1, the mixture comprising the (R)-enantiomer in an excess of 20to 80%, with respect to the (S)-enantiomer.
 17. The mixture according toclaim 16, wherein the excess is 30 to 70%.
 18. A process for themanufacture of levobupivacaine, which comprises racemisation of themixture of enantiomers of a compound of claim 1, said mixture comprisingthe (R)-enantiomer in excess of 20 to 80 % with respect to the(S)-enantiomer, and subsequent resolution.